Excitatory receptors activated by the neurotransmitter L-glutamate are responsible for most fast excitatory synaptic communication in vertebrate nervous systems. In the proposed research the glutamate receptor subtypes specifically activated by N-methyl-D-aspartate (NMDA receptors) will be studied. NMDA receptors are required for many basic functions of the nervous system, including development and memory formation. Imbalanced NMDA Receptor activity has been linked to numerous nervous system disorders, including schizophrenia, Parkinson's disease, Alzheimer's disease, Huntington's disease, stroke, and epilepsy. The unique properties of the ion channel formed by NMDA receptors are essential for its central position in nervous system function and dysfunction. The long-term objectives of the proposed research are to understand the ion channel structures and properties that are about central to NMDA receptor function. NMDA receptors are subject to many forms of physiological regulation. One of the most powerful is block of the ion channel of NMDA receptors by extracellular magnesium ions (Mg about). Block by Mg2+ in turn is strongly regulated by both extracellular and intracellular ions that can permeate the channel of NMDA receptors. To achieve he objectives of the proposed research, the following specific aims will be pursued: (1) examine how the important regulatory ion Ca2+ affects block of the channel of NMDA receptors by Mg2+ (2) determine how the effect of permeant ions on Mg2+ block varies among NMDA receptor subtypes; (3) identify amino acids within the structure of NMDA receptors that are involved in forming the site at which permeant ions bind and affect block by Mg2+ These aims will be achieved through a combination of electrophysiological recording from cells and from single NMDA receptors, computational modeling of NMDA receptor activity, and manipulation of the structure of NMDA receptors using molecular biological approaches. The results of the proposed research will extend our understanding of the structure and operation of NMDA receptors, and thus provide insight into their operation in nervous system physiology and disease.